Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas

项目摘要/摘要 CIC-DUX4融合癌蛋白是一组高度致命的未分化 影响儿童、青少年和青壮年的肉瘤(Aya)。我们最近披露了关键的 CIC-DUX4下游的转录程序驱动包括肿瘤生长在内的恶性表型 和转移。此外，最近的研究表明，Capicua(CIC)蛋白的表达直接 受丝裂原活化蛋白激酶(MAPK)信号通路的调节。我们的长期目标是 实验室将识别和剖析调节融合癌蛋白稳定性和 在人肉瘤中的表达。我们的研究将揭示融合癌蛋白特有的脆弱性， 促进基于精确度的治疗设计，以改善患有普遍致命形式的 肉瘤。这项提议的目标是融合我们在Capicua(CIC)生物学和MAPK信号方面的专业知识 目的：开发首例CIC-DUX4肉瘤的精确治疗方法。我们假设， 基因或药物激活的MAPK会导致CIC-DUX4癌蛋白的降解。我们的 基本原理是基于我们之前的研究，证明了MAPK介导的野生型(非融合)CIC的调节 蛋白质在人类癌症背景下的表达。我们的具体目标将检验以下假设：(目标1) 人ERK与核CIC-DUX4的物理相互作用；(AIM 2)MAPK-ERK通路激活减少 CIC-融合癌蛋白的稳定性，导致降解；以及(目标3)MAPK的药物激活 途径通过CIC-DUX4融合癌蛋白的快速降解而降低肿瘤细胞的存活率。这个 这些发现的意义是非常有影响力的，因为目前还没有针对CIC的有效治疗策略。 DUX4肉瘤，在转移的环境中仍然是致命的。我们的建议是创新的，因为我们 利用我们在MAPK信号转导、转录因子融合和Capicua生物学方面的专业知识，开发出 基于精确的治疗方法直接靶向并降解肉瘤中致命的融合癌蛋白 未得到满足的科学和临床需求。

PROJECT SUMMARY/ABSTRACT The CIC-DUX4 fusion oncoprotein is the molecular hallmark of a highly lethal subset of undifferentiated sarcomas that affects children, adolescents, and young adults (AYA). We have recently revealed critical transcriptional programs downstream of CIC-DUX4 that drive malignant phenotypes, including tumor growth and metastasis. Additionally, recent studies demonstrate that Capicua (CIC) protein expression is directly modulated by the mitogen-activated protein kinase (MAPK)-signaling pathway. The long-term goal of our laboratory is to identify and dissect the critical molecular pathways that regulate fusion oncoprotein stability and expression in human sarcoma. Our studies will reveal fusion oncoprotein-specific vulnerabilities that can facilitate precision-based therapeutic design to improve outcomes for patients with universally lethal forms of sarcomas. The objective of this proposal is to fuse our expertise in Capicua (CIC) biology and MAPK signaling to develop the first precision-based therapeutic approach for CIC-DUX4 sarcomas. We hypothesize, that genetic or pharmacologic MAPK activation will lead to the degradation of the CIC-DUX4 oncoprotein. Our rationale is based on our prior studies demonstrating MAPK-mediated regulation of wild-type (non-fused) CIC protein expression in the context of human cancer. Our specific aims will test the following hypotheses: (Aim 1) human ERK physically interacts with nuclear CIC-DUX4; (Aim 2) MAPK-ERK pathway activation decreases CIC-fused oncoprotein stability, leading to degradation; and (Aim 3) pharmacologic activation of the MAPK pathway decreases tumor cell survival through rapid degradation of the CIC-DUX4 fusion oncoprotein. The significance of these findings are highly impactful, as there are no effective therapeutic strategies to target CIC- DUX4 sarcomas, which remain lethal in the metastatic setting. Our proposal is innovative because we are leveraging our expertise in MAPK-signaling, transcription factor fusions, and Capicua biology to develop a precision-based therapeutic approach to directly target and degrade a lethal fusion oncoprotein in sarcoma, an unmet scientific and clinical need.